Wernicke encephalopathy complicating lymphoma therapy: case report and literature review.

Abstract: Thiamine deficiency can occur in any disease that results in inadequate intake or excessive loss of vitamin [B.sub.1]. In addition to increased thiamine consumption secondary to high cell turnover, cancer patients frequently have reduced oral intake as a direct result of their cancer or from cancer treatments. However, Wernicke encephalopathy (cerebral Beriberi), a clinical manifestation of thiamine deficiency, has rarely been associated with cancer patients. We report a case of Wernicke encephalopathy in a nonalcoholic patient with lymphoma. Although thiamine deficiency rarely potentiates clinical sequelae in cancer patients, it is important to recognize the risk and the clinical signs and manifestations so that prompt therapy can be initiated to reverse morbidity.

Key Words: Wernicke encephalopathy, thiamine, thiamine deficiency, lymphoma, vitamin [B.sub.1]

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Wernicke encephalopathy can be a severely debilitating disease, but is also easily and completely reversed when recognized and treated correctly. Thiamine deficiency as a result of cancer-induced anorexia and cachexia is often overlooked. We describe a 56-year-old man who presented with Wernicke encephalopathy as a manifestation of non-Hodgkin lymphoma. Furthermore, we examine the factors responsible for its development, as well as a literature review of the etiology, pathophysiology, and management of thiamine deficiency.

Case Report

A 56-year-old male presented complaining of two to three months of malaise, decreased appetite with an associated 50-pound weight loss, and diffuse abdominal pain. Over the two weeks preceding his presentation, he developed jaundice, generalized lymphadenopathy, and persistent nausea and vomiting that significantly limited his oral intake. His past medical history was insignificant. He was not on any medications. He was a nonsmoker, nondrinker, and had an unremarkable family history. Physical examination showed a well developed, vitally stable, icteric, afebrile male with generalized, non-tender adenopathy. Laboratory studies revealed abnormal liver enzymes: AST 183 (normal; 5-34), ALT 203 (normal; 5-55), alkaline phosphatase 819 (normal; 40-150), and a total bilirubin of 6.1 (0.2-1.2). Left cervical lymph node biopsy demonstrated diffuse, large B-cell lymphoma (CD 20 positive). Human immunodeficiency virus testing was negative. CAT scans demonstrated generalized adenopathy and gastric and renal involvement. The patient underwent esophagogastroscopy with gastric biopsy positive for B-cell non-Hodgkin lymphoma. Bone marrow biopsy was negative for involvement. He was treated with CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab) with doxorubicin and vincristine held secondary to significant hepatic dysfunction.

He returned 19 days following his initial chemotherapy complaining of progressive difficulty walking and blurred vision for one week. He had no headache, fevers, or neck pain. Physical examination was remarkable for coarse vertical nystagmus (at rest and with intention). Superficial adenopathy was no longer palpable. His hepatic abnormalities (transaminases and bilirubin) were normal. MRI with and without contrast of the brain and stem showed no significant findings. Spinal fluid examination was unremarkable. He began treatment with daily empiric IV thiamine, and within 48 hours, all of the patient's neurologic symptoms had resolved. He was diagnosed with Wernicke encephalopathy. He received cycle two of CHOP-R and was discharged on oral thiamine replacement. He was seen in the clinic 10 weeks after thiamine treatment and remained asymptomatic.

Discussion

Thiamine (vitamin [B.sub.1]) is a water-soluble vitamin found primarily in fortified cereals, pasta, whole grains, lean meats, fish, dried beans, peas, and soybeans. Dairy products, fruits, and vegetables have minimal thiamine. Deficiency is associated with chronic alcoholism, food faddism, inadequate thiamine intake, accelerated loss, or defective utilization. (1) Thiamine deficiency associated with malignancy has been documented in several tumors, sporadic clinical case reports, and in a number of patients with fast-growing hematologic malignancies, especially pediatric cancers. (2,3) Research in cell culture and animal models has revealed a high requirement for thiamine in rapidly dividing cells. (4) Seligmann et al (2) prospectively studied patients with B-chronic lymphocytic leukemia and found 35% of their patients to have subclinical thiamine deficiency. Basu and Dickerson (5) described higher urinary excretion of thiamine in patients with breast and bronchial tumors compared with controls. Cancer patients have a combination of rapid cell turnover, poor oral intake due to both disease effect and chemotherapy, and possibly increased excretion--all of which contribute to vitamin [B.sub.1] deficiency.

Wernicke encephalopathy (WE), or cerebral beriberi, is a manifestation of thiamine deficiency. Wernicke encephalopathy presents clinically as the classic triad of encephalopathy, oculomotor dysfunction, and gait ataxia; however, the combination of all three is only observed in one-third of patients with WE. Disorientation, indifference, and inattentiveness are the main findings which comprise the encephalopathy. Nystagmus, including vertical nystagmus, is the most common of the oculomotor manifestations. Lateral rectus palsy, conjugate gaze palsies, and papillary abnormalities may also occur. Gait disturbance most likely is caused by a combination of polyneuropathy, cerebellar involvement, and vestibular dysfunction. (6) Other signs, including stupor or coma, hypotension, hypothermia, and malnutrition, are also observed. (6,7) Our patient presented with both gait ataxia and oculomotor dysfunction.

Based on an autopsy series in 106 alcohol abusers, the Caine criteria were devised for the diagnosis of Wernicke encephalopathy. (8) The presence of any two of the following four criteria are diagnostic of WE, according to the Caine criteria: dietary deficiency, oculomotor abnormalities, cerebellar dysfunction, and either altered mental status or mild memory impairment. The diagnostic sensitivity was increased to 85% when using these criteria as compared with a 22% diagnostic sensitivity for the classic triad. Although these criteria are more sensitive than the classic triad, sensitivity needs to be increased due to the high morbidity and mortality of the disorder. The Caine criteria, however, were not intended for the diagnosis of Wernicke encephalopathy in nonalcoholics. (8)

While WE is primarily a clinical diagnosis, laboratory studies and neuroimaging may be helpful. Usually the disease is recognized when an alcoholic presents with the classic triad. But based on autopsies done, many patients will present without one or more elements of the triad, further complicating the diagnosis. (7) While no laboratory studies are diagnostic for vitamin [B.sub.1] deficiency, some tests may be beneficial. Measuring erythrocyte thiamine transketolase before and after the addition of thiamine pyrophosphate will detect a deficiency in thiamine. The diagnosis is established with a low level of the transketolase and a more than 25% stimulation. This test, however, is frequently not available. (9) Thiamine or thiamine pyrophosphate levels can also be measured in serum by chromatography; however, in symptomatic patients, the sensitivity and specificity of these tests are unclear. (10) Rapid recovery after the administration of IV thiamine is in itself diagnostic of thiamine deficiency.

While imaging studies are not required, some can rule out other diagnoses or supply evidence of WE. CT scan or MRI abnormalities in a small number of patients have been reported. (11) Symmetric, low-density abnormalities in the diencephalon, midbrain, and periventricular regions that enhance following contrast injection may be seen on CT scan. (12,13) However, a normal CT does not rule out the diagnosis. MRI appears to be more sensitive in detecting neural lesions in cases of acute WE. (14) One specific finding in patients with chronic lesions of WE is mammillary body atrophy. (15) The reduction in volume of the mammillary bodies cannot be found in controls, patients with Alzheimer disease, or alcohol abusers without a history of WE. Furthermore, atrophy of the mammillary bodies can be recognized by MRI in approximately 80% of alcohol abusers with a history of classic WE and can be seen within one week of onset. (15-18)

The pathophysiology of Wernicke involves a deficiency in thiamine which is a cofactor for several key enzymes important in energy metabolism. During periods of high metabolic demand and high glucose intake, thiamine is needed as a cofactor for several enzymes, including transketolase, [alpha]-ketoglutarate dehydrogenase, and pyruvate dehydrogenase. (6) Therefore, WE can be precipitated in susceptible patients by administration of IV glucose before thiamine supplementation. (19) The role of thiamine in WE has been observed by inducing thiamine deficiency in rats with the thiamine antagonist pyrithiamine. The result is a sequence of ataxia, loss of the righting reflex, and convulsions. (20)

Although thiamine plays a part in cerebral energy utilization, the etiology of brain lesions in WE is unclear. However, it has been proposed that thiamine deficiency begins the process of neuronal injury by halting metabolism in regions of the brain with high thiamine turnover and high metabolic requirements. Also, breakdown of the blood brain barrier, excitotoxicity of the NMDA receptor, and increased reactive oxygen species have been proposed in thiamine deficiency-induced neurotoxicity. (21)

Treatment for Wernicke encephalopathy consists of the use of IV thiamine, which should begin when the diagnosis is suspected. The recommended dosage is 100 mg IV or IM for five consecutive days. Since the administration of glucose without thiamine can precipitate or aggravate WE, thiamine should be given before glucose. As absorption of thiamine from the GI tract is inconsistent in alcoholic or malnourished patients, oral administration of thiamine should be avoided in a patient suspected of having WE. Following parenteral administration of thiamine, patients should be given oral thiamine daily until they are no longer considered at risk. (22-26)

Conclusion

Vitamin [B.sub.1] deficiency has rarely been described in patients with lymphoma. As a direct result of his disease, our nonalcoholic patient developed a deficiency of thiamine through decreased oral intake and increased cell turnover. Prompt diagnostic consideration for Wernicke encephalopathy and empiric thiamine allowed our patient to have minimum morbidity and rapid reversal of his symptoms. In cancer patients demonstrating changes in cognitive function, gait ataxia, or oculomotor dysfunction, thiamine deficiency should be included in the differential diagnosis.

Text Boxes

Decreased oral intake and increased cell turnover may lead to a thiamine deficiency in cancer patients.

Cancer patients demonstrating changes in cognitive function, gait ataxia, or oculomotor dysfunction should be checked for thiamine deficiency.

References

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Scott Boniol, MD, Molly Boyd, MD, Rachel Koreth, MD, and Gary V. Burton, MD

From Feist-Weiller Cancer Center, Louisiana State University Health Science Center, Shreveport, LA.

Reprint requests to Dr. Gary V. Burton, Feist-Weiller Cancer Center, Louisiana State University Health Science Center, 1501 Kings Highway, Shreveport, LA 71130. Email: [e-mail]

Accepted February 12, 2007.

RELATED ARTICLE: Key Points

* Wernicke encephalopathy is a reversible condition caused by thiamine deficiency.

* Thiamine deficiency occurs in any disease state that causes inadequate intake or excessive loss of vitamin [B.sub.1].

* Wernicke encephalopathy manifests as encephalopathy, oculomotor dysfunction, and gait ataxia.

* Treatment of Wernicke encephalopathy requires intravenous thiamine prior to any glucose-containing solutions so as not to precipitate the disease.